10-73011033-C-G

Variant names:

• chr10-73011033-C-G
• rs1212906330
• NM_001017962.3:c.1373G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017962.3(P4HA1):​c.1373G>C​(p.Ser458Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: P4HA1 NM_001017962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

P4HA1 (HGNC:8546): (prolyl 4-hydroxylase subunit alpha 1) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA1	NM_001017962.3	c.1373G>C	p.Ser458Thr	missense_variant	Exon 13 of 15	ENST00000394890.7	NP_001017962.1
P4HA1	NM_000917.4	c.1373G>C	p.Ser458Thr	missense_variant	Exon 13 of 15		NP_000908.2
P4HA1	NM_001142595.2	c.1373G>C	p.Ser458Thr	missense_variant	Exon 14 of 16		NP_001136067.1
P4HA1	NM_001142596.2	c.1319G>C	p.Ser440Thr	missense_variant	Exon 12 of 14		NP_001136068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA1	ENST00000394890.7	c.1373G>C	p.Ser458Thr	missense_variant	Exon 13 of 15	1	NM_001017962.3	ENSP00000378353.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1373G>C (p.S458T) alteration is located in exon 14 (coding exon 12) of the P4HA1 gene. This alteration results from a G to C substitution at nucleotide position 1373, causing the serine (S) at amino acid position 458 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;D;.;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.3	L;L;L;.;L
PhyloP100		7.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.26
Sift	Benign	0.11	T;T;T;D;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.96	D;.;D;.;.
Vest4		0.69
MutPred		0.75		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);
MVP		0.74
ClinPred		0.95	D
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.41
gMVP		0.94
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1212906330; hg19: chr10-74770791;